The present invention relates to a series of new oligopeptides which have renin-inhibitory and, hence, hypotensive activities and thus are of particular value in the diagnosis and treatment of hypertension induced by failures in the renin-angiotensin system. The invention also relates to the preparation of such compounds and to their use in such treatment.
There is considerable evidence that reduction of elevated blood pressure reduces the risks of morbidity and mortality. Elevated blood pressure (hypertension) can be caused by a variety of factors and a large number of drugs is available for the treatment of hypertension, the drug of choice being dictated in large measure by the cause of the hypertension.
Angiotensin I is a polypeptide formed in vivo by the action of renin upon a plasma protein; it is converted in vivo to angiotensin II by the action of ACE (angiotensin converting enzyme). Angiotensin II causes constriction of the arterioles and can produce hypertension. Hypertension of this type can be reduced by reducing the plasma concentration of angiotensin II which, in turn, can be achieved by inhibiting the activity of renin. The number of available drugs having this type of inhibitory activity is very limited, and, to date, no such drug is commercially available. A variety of peptide derivatives having this type of activity is known.
Examples of known peptide derivatives possessing renin inhibitory activity include, for example, the tetrapeptide, tripeptide and like derivatives as described, for example, in Japanese Patent Publication No. Sho 58-39149, in Japanese Patent Kokai Publication No. Sho 61-275256, in European Patent Publications No. 152 255, 173 481, 184 550, 236 734, 278 158 and 297 816, and in WIPO Publication No. 87/04 349. Those prior art compounds believed to be closest to the compounds of the present invention, are disclosed in European Patent Publications No. 184 550, 236 734 and 278 158.
A serious disadvantage common to almost all of the known renin-inhibitory oligopeptides, including many of those mentioned in the previous paragraph, is that, in practice, it is necessary to administer them by parenteral routes, e.g. by injection, as suppositories or even by inhalation. This applies even in those cases where the compounds have been suggested for oral use, since it has often subsequently been found that they either are insufficiently stable to enzymes, e.g. esterases, present in the digestive system or are inadequately absorbed from the stomach and/or intestines or both. Of course, this poor stability in the digestive system is expected with oligopeptides, as the mammalian digestive system is specifically designed to break down compounds of that type. Consequently, even if the compounds can be administered orally, such high doses are necessary in order to make up for poor absorption and/or losses caused by digestion as to make oral administration impractical.
It is, of course, well known that the oral route is the preferred route of administration, particularly where (as with the drugs with which the present invention is concerned)drugs are intended for self-administration by the patient, generally over a long period of time.
Hence, the inability of many of the known renin-inhibitory oligopeptides to be effective when administered via the oral route is a serious disadvantage to their practical therapeutic use, despite what may appear to be their useful activities.
We have now discovered a series of peptide derivatives having a very marked ability to inhibit the activity of renin, which ability is believed to be significantly better than that of the prior art compounds. However, most significantly and surprisingly, the compounds of the invention have been found to have excellent absorptive properties (especially through the intestinal and digestive tracts) upon oral administration, quite contrary to what has been generally experienced with most of the prior art oligopeptide compounds. Moreover, certain of the compounds of the invention have additionally and unexpectedly demonstrated very good stability on oral administration (i.e. they are stable to digestive enzymes, e.g. esterases).
These unexpected properties render the compounds of the invention especially suited to oral administration, as well, of course, as to the more traditional parenteral routes of administration.